News and commentary on what we consider to be the top new schizophrenia research developments most relevant for families, care takers and people who have schizophrenia. Hosted by Farzin Irani (PHD candidate), and Jacob Ballon, (MD candidate).

December 23, 2004

Schizophrenia and Paternal Age

Paternal age and risk of developing schizophrenia

Nobody knows why certain people get schizophrenia. However, there are many possibilities that have been investigated. There is evidence of a genetic component to developing schizophrenia, but that precise link is currently under investigation and while there are certain spots that appear relevant, it is not known exactly what the mechanism is precisely.

Many articles, of which these are some, have postulated that there is an increased risk of schizophrenia based upon an increased age of the father. This theory is not unique to schizophrenia. Diseases such as achondroplasia (a type of dwarfism), certain cancers, and other disorders are linked to increased paternal age. Increased maternal age is linked to increased risk of Down’s syndrome and other developmental disorders. The reason that increased age is thought to be relevant to developmental and genetic diseases is complex. As men age, they produce billions of sperm. With each sperm that is generated, there is a risk that the man’s DNA will not be translated exactly perfectly. These are called mutations and these mutations increase with age. There are many mechanisms that prevent mutations and they are thought to become less precise with age. Therefore, older men are thought to have what are called, “de novo” mutations more as they age. De novo means that they are new and spontaneous mutations. They are considered spontaneous because they are not seen in the previous generations of the family. Were it not for spontaneous mutations, evolution would eliminate many genetic diseases through lack of reproduction of the person with the disorder.

It is difficult to explain what might be unique about paternal DNA that might cause these effects. It is postulated that it might be linked to the father's X-chromosome. Maternal DNA is easier to follow because of a type of DNA called "mitochondrial" DNA. That is a special type of DNA associated with a part of the cell called the mitochondria. This is nearly exclusively passed down from the mother to the child rather and almost never has a paternal contribution. It is more difficult to trace paternal DNA patterns.

There are some things that are difficult to sort out with this research however. Older fathers are typically having children with older mothers. There are statistical methods to control for the age of mothers while looking at rates of schizophrenia. Using these methods, they were able to find that paternal age was more statistically relevant than maternal age.

Lastly, when looking at epidemiological studies of risk, it is important to keep some principles in mind. First, these studies show associations and while they usually provide a hypothesis (educated guess) as to what the cause is based on these association, they are not able to make the definitive cause known. Therefore, it is not certain that other factors not thought of by investigators, are related to older fathers and schizophrenia and that in fact the father’s age is just part of the story. An example of this was when it was found that coffee drinking was linked with certain cancers. It turned out that people who drank coffee were more likely to be using cigarettes and the cigarettes were responsible for the cancer risk and not the coffee, even though there was an association with coffee and cancer nonetheless. Second, the generally considered risk of schizophrenia in the general population is approximately 1% of the population. This is a large risk compared to certain diseases, but is still small. Therefore, when a risk factor is doubled, it is still a small risk overall, meaning that there are likely other factors besides just paternal age that are part of the picture, but these studies are focusing on paternal age. Lastly, these studies all look at schizophrenia diagnosed at the time of the study. They usually look for several years through the main time of diagnosis (late teens to twenties.) However, they do miss the later onset schizophrenia which may be a lower proportion of patients, is nonetheless important.

This study looked at a population of 750,000 people in Sweden born between 1973 and 1980. They looked at patients who were admitted with a schizophrenia diagnosis. They found that fathers over the age of 45 had an approximately two-fold increase in schizophrenia risk. They showed no increased risk with fathers over fifty, but the sample was too small to draw a conclusion. Since they only looked at hospitalized patients, it is possible that they may have missed certain cases that did not present as inpatients.

This research group used a database generated in Israel. They looked at 90,000 people born and followed for 30 years. In Israel, there is a database kept on all citizens regarding psychiatric illness. Using these databases, they found that as fathers aged, for every ten years above 30, there was a 40% increase in risk. This was up to 2.5 fold risk in fathers over 50 (though this was a small enough sample to be as low as 1.5 fold increased risk.) This study also looked at years of marriage as another correlate and found that the risk of schizophrenia decreased with longer marriages. They ultimately believe that approximately 26% of schizophrenia cases can be attributed to paternal age.

This study was done as a "case-control" study of a Danish population. This means that the authors took people who already were diagnosed with schizophrenia (cases), and compared with age, sex, demographic matched people without schizophrenia (controls.) They looked at 7700 cases and had 25 controls for each case (192,000). This way, they are able to try and compare what is different in the groups while still having many similarities and therefore fewer variables. They seperated out cases that also had a family history to help to isolate the sporadic mutations verus inherited cases.The authors found that with fathers over 50 years of age the risk was approximately two fold the risk of younger parents. They also found that the risk was increased for females with older fathers than for males, though this was only a slight difference.

This is another case-control study that looked at a small population of people in Stockholm. They also found an approximately double risk of schizophrenia with paternal age greater than fifty years old no impact on risk based on the maternal age. One potential problem in this study is that while they looked at maternal psychotic illness history, they were unable to do so with the fathers and therefore some inherited cases may have been included in that respect.

Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia.

Schizophr Res. 2004 Apr 1;67(2-3):227-36.

This study did another population based study. They used populations from all of Denmark; Malmo, Sweden; and Brisbane, Australia. In both the Swedish and Danish populations they found approximately 2 fold difference in fathers above the age of 35 years old. However, in the Australian sample, they were unable to find a difference with age though this group was far smaller than the other groups and may not have had the statistical power needed to find a difference.

This is a cohort study, meaning that they looked at a large population at birth and then followed the whole group and recorded who among the group developed schizophrenia. Then, they looked at the various variables they wanted to test (paternal age for example) and made conclusions. They looked at a group of 50000 births in Sweden and used hospital discharge diagnoses to determine the cases of schizophrenia in the cohort. This group also found a between 2 and 3 fold increase in risk with fathers over the age of fifty. These authors postulated that perhaps there were social factors in fathers that had children at older ages that might predispose their children to developing schizophrenia. To test this hypothesis, the authors of the study controlled for social integration factors, parental drug use and IQ. These factors did not have any influence on the data and the authors then concluded that social factors of older fathers was less likely to have an influence than the de novo mutations postulated by the other authors above.

This is another small cohort study in which the authors looked at approximately 20,000 live births from Kaiser Family Health in Alameda, California. They followed the population for an average of thirty years. This is the first study of patients in the United States amongst those above. It adds to the data already from Scandinavia and Israel and makes the results more generalizable to the overall population. The authors here found that if they controlled for numerous other variables, the rate of increased risk of schizophrenia increased about 80% for each decade older the father was after age 20. This put the age of forty at a more than 2 fold increased risk. However, this was a smaller study than some of the others and many of the potential subjects were excluded for various reasons. Nonetheless, this study demonstrates a "dose-response" relationship meaning that it is possible to demonstrate a linear increase in risk that correlates with a similar linear increase in age.

In this study the authors looked at consecutive admissions to the New York State Psychiatric Institute in New York City. They did comprehensive interviews and family histories on each patient and analyzed the results. They found that families without a history of schizophrenia had a higher risk of schizophrenia in older parents. They also attempted to describe differences in disease process amongst familial versus sporadic cases, but that would require further research to be fully described.

I hope this review of the topic was interesting. There are a lot of possible causes of schizophrenia and nobody knows what is most important. These studies are but one theory of something that is related to increased risk of schizophrenia, but it is merely an association and the full mechanism remains to be described.